In parallel with bacteriological studies, human genetic analyses have shown that several mutations are associated with Crohn's disease. The genes concerned allow the formation of proteins that are implicated in inflammation or the elimination of bacteria that are naturally present in the body.
In patients with Crohn's disease, the mucosa of the small intestine is abnormally colonised by pathogenic strains of the bacterium Escherichia coli. Their persistence in the intestine may be the reason for the chronic inflammation observed in Crohn's disease, which led the research team to question the causes of this persistence which was suggestive of a defect in bacterial elimination.
Based on these observations, the scientists focused on a gene, IRGM, that is implicated in the cell process called autophagy1, and which is able to eliminate the bacteria present in host cells. Surprisingly, a silent mutation (i.e. which modifies the gene sequence without modifying the sequence of the final protein) in the IRGM gene was associated with an increased risk of developing Crohn's disease. This mutation was found in one in five patients.
In fact, this so-called silent mutation has major consequences. This study was able to demonstrate a defect in the regulation of IRGM protein expression, which was thus over-expressed and could no longer correctly eliminate intracellular pathogenic bacteria in patients with Crohn's disease.
These new findings reveal that so-called silent mutations, hitherto thought to have no effects, may in fact be implicated in potentially serious diseases. This opens the way to a clearer understanding of the onset of a variety of diseases. In Crohn's disease, it provides an additional opportunity to study the development of new treatments.
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Marked proliferation of adherent and invasive Escherichia coli bacteria (labelled green) in epithelial cells displaying a defect in the autophagic process
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References:
A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn’s disease. NATURE Genetics, published online 30 January 2011; doi:10.1038/ng.762. Patrick Brest1,2, Pierre Lapaquette3,4, Mouloud Souidi5,6, Kevin Lebrigand2,7, Annabelle Cesaro1,2, Valérie Vouret-Craviari1,2, Bernard Mari2,7, Pascal Barbry2,7, Jean-François Mosnier8, Xavier Hébuterne1,2,9, Annick Harel-Bellan5,6, Baharia Mograbi1,2, Arlette Darfeuille-Michaud3,4,12 & Paul Hofman1,2,10–12
1INSERM ERI-21, EA4319, Faculty of Medicine, Nice, France. 2University of Nice Sophia-Antipolis, Nice, France. 3Clermont Université, Université d’Auvergne, Clermont-Ferrand, France. 4Institut National de la Recherche Agronomique (INRA), USC-2018, Clermont-Ferrand, France. 5University Paris Sud, Epigenetics and Cancer, Villejuif, France. 6Centre National de la Recherche Scientifique (CNRS), Villejuif, France. 7CNRS UMR 6097, Institute of Molecular and Cellular Pharmacology, Valbonne, France. 8EA4273, University of Nantes, Nantes, France. 9Department of Gastroenterology, Archet Hospital, Nice, France. 10Biobank Unit, Pasteur Hospital, Nice, France. 11Laboratory of Clinical and Experimental Pathology, Pasteur Hospital, Nice, France. 12
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